CLINICAL UPDATE UPDATE Coeliac disease: the great imitator John M Duggan “Know syphilis in all its manifestations and all other things ABSTRACT clinical will be added unto you.”1 ■ Coeliac disease (CD) is caused by a complex immunological WHEN THE SUPREME CLINICIAN William Osler wrote this, response provoked by grain protein in susceptible people. he was drawing attention to the ubiquity of syphilis and the remarkable range of its late-stage manifestations, today ■ The majority of people with CD are symptom-free adults; virtuallyThe unknown.Medical Journal However, of Australia I argue ISSN: that 0025-729X its place has been the remainder are prone to a bewildering variety of signs taken17 by May coeliac 2004 180disease 10 524-526 (CD), another great imitator. As a and symptoms, ranging from infertility to type 1 diabetes. diagnostic©The challenge,Medical JournalCD is ofthe Australia“syphilis” 2004 of the 21st ■ Many patients with undiagnosed CD spend years seeking century.www.mja.com.au Clinical Update help for complaints such as chronic tiredness or mild Western civilisation owes much of its foundation to a abdominal symptoms. strange molecular rearrangement of the chromosomes of wild grasses in the Middle East to produce a high-protein, ■ In primary care, an appropriate target group to test for CD is high-yielding grain — wheat — with six sets of chromo- people with anaemia (especially women), chronic tiredness, somes. This enabled the nomads to settle down with some non-specific abdominal symptoms (including so-called assurance of a regular food supply and time to think and “irritable bowel syndrome”), or a family history of CD. develop skills such as writing. ■ The response to an appropriate gluten-free diet is often This progress, however, came at a price. Gliadin, the life-transforming for symptomatic patients. principal wheat protein, presented to sensitised T cells in ■ Positive serological tests for CD require confirmation by conjunction with HLA-DQ2 or HLA-DQ8 antigen, leads to duodenal biopsy and, if confirmed, referral to a dietitian and the production of cytokines. The cytokines cause tissue a coeliac society, followed by a life-long gluten-free diet. damage within the mucosa and activate plasma cells to produce antibodies to gliadin, tissue transglutaminase and MJA 2004; 180: 524–526 endomysium. Wheat, rye, barley and, to a minor extent, oats have progressively lesser amounts of the toxic amino acid sequence. Why only a small proportion of the popula- dermatitis are related to gluten intolerance, although the tion who are bearers of HLA-DQ2 and HLA-DQ8 produce duodenal changes may only manifest themselves after pro- these changes is unknown, as is why cigarette smoking longed high intake of gluten.34 With a gluten-free diet, the 2 reduces the risk of CD by 80%. However, what we are condition resolves and the intense itchiness subsides. progressively learning is that the ill effects of the molecular Another association is with type 1 diabetes. The preva- events extend far beyond the small-bowel mucosa. For every lence of CD in people with type 1 diabetes is about 3 to classical thin, pale, pot-bellied patient with steatorrhoea, 8%,4 while the prevalence of type 1 diabetes in people with there are many with few or no symptoms, amounting in CD is about 5%.32 However, there are no data on whether most North American and European societies to 0.5% to patients with diabetes and CD experience improvement in 1.0% of the population, particularly those of northern their diabetes symptoms in response to a gluten-free diet. 3 European ancestry. Another group of associations is exemplified by the It is becoming evident that a host of disorders in many anaemias — essentially a complication of malabsorption, systems are aetiologically related to the presence of CD, particularly of iron and folate. These conditions respond often manifesting themselves in the context of an inapparent fully to nutrient replacement. coeliac state (Box 1). For some, such as fatty liver However, the largest, possibly most important and least “transaminitis” or hepatitis, the link is clear. Our research understood group of diseases that appear to have links with (as yet unpublished) shows that about 40% of both children CD are those with a statistical association, such as epi- and adults with this disorder (who typically have laboratory lepsy,32 the neuropathies32 and myelopathies,10 the and histological evidence of CD but few clinical signs) have ataxias,12 and male and female infertility.16,17 With these liver abnormalities that resolve within a few months on an conditions, the story is only beginning to unfold, and appropriate diet. responses to diet are less evident. Dermatitis herpetiformis is another condition that is Such associations are only likely to be detected, and clearly linked to CD. Most, if not all, cases of this form of their nature and course unravelled, if physicians have a much lower threshold for suspecting CD behind many different clinical syndromes (Box 2). By performing sim- Princeton Medical Centre, Hamilton, NSW. ple and relatively inexpensive laboratory tests — such as John M Duggan, MD, FRACP, FRCP, Physician. Reprints will not be available from the author. Correspondence: Professor tests for transglutaminase antibody (sensitivity, 93%; spe- John M Duggan, Princeton Medical Centre, 60 Lindsay Street, Hamilton, cificity, 99%) and the endomysial antibody (sensitivity, NSW 2303. [email protected] 85%–98%; specificity, 97%–100%) — followed by endo- 524 MJA Vol 180 17 May 2004 CLINICAL UPDATE 1: Clinical disorders associated with coeliac disease 2: Coeliac disease: mode of presentation, and prevalence of the various symptoms/findings Gastrointestinal Haemopoietic among presenting patients35,36 Liver disease “transaminitis”, Anaemia (iron, folate and 21 hepatitis, fatty liver, primary vitamin B12 deficiency) Proportion of biliary cirrhosis, cirrhosis* Coagulation disorders from patients with this Prevalence of Recurrent aphthous mouth vitamin K deficiency21 Mode of presentation primary presentation symptom/finding 4 4 ulcers IgA deficiency Anaemia 10%–18% 12%–22% Irritable bowel syndrome5 20 Hyposplenism Feeling “tired all the 20% 58% 6 Lymphocytic gastritis T-cell lymphoma20 time” Ulcerative jejunitis7 Malabsorption/bowel 43% 60% 8 Locomotor Reflux oesophagitis symptoms Osteopenia22 Adenocarcinoma of small Coeliac disease in 13% 5%–10% 9 Arthralgia/arthritis23,24 bowel first-degree relative(s) Neurological Dermatological Symptoms in na 50% 25 Peripheral neuropathy10 Dermatitis herpetiformis childhood 26 Epilepsy11 Psoriasis Incidental finding at 8% na endoscopy Ataxia12 Brown pigmentation of face and buccal mucosa27 Myelopathy10 na = not applicable. Dental Psychiatric 28 13 Defects in tooth enamel Depression and duodenal biopsy and referral to a coeliac society if CD 14 Schizophrenia Genetic is indicated. Given that GF diets are complex, lifelong, Down syndrome29 Endocrine expensive and socially disruptive, they must always be 15 preceded by histological proof from a biopsy. Nevertheless, Type 1 diabetes Cardiovascular the potential benefits for some patients may be enormous. Infertility in men and Cardiomyopathy30 women16,17 In the Australian context, an appropriate strategy is to Recurrent abortion18 Other request testing for endomysial and transglutaminase anti- 31 Thyroid disorders19 Alopecia areata bodies, ensuring that the laboratory tests for IgG antibodies 32 Addison’s disease19 Sjögren’s syndrome in patients who have IgA deficiency, which is common in Finger clubbing27 patients with CD.37 An appropriate group of patients to Renal Pharyngeal and oesophageal target would be those who have the type of symptoms IgA nephropathy20 carcinoma33 described above in the UK study.36 In summary, there can be little doubt that the trans- * Duggan JM and Duggan AE (unpublished observations). glutaminase/endomysial antibody assay should be part and parcel of the diagnostic armamentarium of every physician, scopic duodenal biopsy in antibody-positive patients, the given that CD can manifest as a disturbance of function of disease is readily diagnosed. virtually any body system. A priori, there must be many Possibly the clearest data on a feasible approach to the other associations yet to be discovered. disease are given in a study in nine general practices in the United Kingdom.36 The study found 30 patients with CD in a target group of 1000 adults with major complaints of Competing interests feeling “tired all the time”, having abdominal symptoms or None identified. having a positive family history of CD. While universal screening for CD may not be feasible, or indeed appropri- ate, the study shows that screening patients with one or References more of these symptoms may be a practicable alternative for 1. Bean WB. Sir William Osler: aphorisms, 133. In: Silverman MB, Murray TJ, Bryant discovering more cases of undiagnosed CD. However, there CS, editors. The quotable Osler. Philadelphia: American College of Physicians, are a number of caveats. While the patient with long-term American Society of Internal Medicine, 2002: 145. lethargy and folate or iron deficiency in the presence of a 2. Suman S, Williams EJ, Thomas PN, et al. Is the risk of adult coeliac disease causally related to cigarette exposure? Eur J Gastroenterol Hepatol 2003; 15: reasonable diet is likely to undergo life-transforming change 995-1000. on a gluten-free (GF) diet with appropriate supplementa- 3. Fasano A, Berti I, Gerarduzzi T. Prevalence of celiac disease in at-risk and not-at- tion, the imposition of a GF diet for the chance finding of risk groups in the United States. Arch Intern Med 2003; 163: 286-292. CD in an effectively symptom-free patient may be a disserv- 4. Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med 2002; 346: 180-187. 5. Sanders DS, Carter MJ, Hurlstone DP, et al. Association of adult coeliac disease ice. This is especially so for many of the associated disorders with irritable bowel syndrome: a case-control study in patients fulfilling ROME II such as type 1 diabetes, for which we at present lack criteria referred to secondary care.